Journal
STRUCTURE
Volume 12, Issue 1, Pages 21-30Publisher
CELL PRESS
DOI: 10.1016/j.str.2003.11.024
Keywords
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Funding
- NCRR NIH HHS [5P41RR05969] Funding Source: Medline
- NIBIB NIH HHS [8-R01EB00249-09] Funding Source: Medline
- NIGMS NIH HHS [5T32GM08268, 1-R01GM60946] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [P41RR005969] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB000249] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008268, R01GM060946] Funding Source: NIH RePORTER
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Cells can switch the functional states of extracellular matrix proteins by stretching them while exerting mechanical force. Using steered molecular dynamics, we investigated how the mechanical stability of FnIII modules from the cell adhesion protein fibronectin is affected by natural variations in their amino acid sequences. Despite remarkably similar tertiary structures, FnIII modules share low sequence homology. Conversely, the sequence homology for the same FnIII module across multiple species is notably higher, suggesting that sequence variability is functionally significant. Our studies find that the mechanical stability of FnIII modules can be tuned through substitutions of just a few key amino acids by altering access of water molecules to hydrogen bonds that break early in the unfolding pathway. Furthermore, the FnIII hierarchy of mechanical unfolding can be changed by environmental conditions, such as pH for FnIII(10), or by forming complexes with other molecules, such as heparin binding to FnIII(13).
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